Moderate to severe atopic dermatitis in children: focus on systemic Th2 cytokine receptor antagonists and Janus kinase inhibitors

Abstract

Atopic dermatitis (AD) is a lifelong disease that markedly impairs quality of life. AD is considered a starting point of the "atopic march," which begins at a young age and may progress to systemic allergic diseases. Moreover, it is strongly associated with comorbid allergic and inflammatory diseases including arthritis and inflammatory bowel disease. Understanding the pathogenesis of AD is essential for the development of targeted therapies. Epidermal barrier dysfunction, immune deviation toward a T helper 2 proinflammatory profile, and microbiome dysbiosis play important roles via complex interactions. The systemic involvement of type 2 inflammation, wheather acute or chronic, and whether extrinsic or intrinsic, is evident in any type of AD. Studies on AD endotypes with unique biological mechanisms have been conducted according to clinical phenotypes, such as race or age, but the endotype for each phenotype, or endophenotype, has not yet been clearly identified. Therefore, AD is still being treated according to severity rather than endotype. Infancy-onset and severe AD are known risk factors leading to atopic march. In addition, up to 40% of adult AD are cases of infancy-onset AD that persist into adulthood, and these are often accompanied by other allergic diseases. Therefore, early intervention strategies to identify high-risk infants and young children, repair an impaired skin barrier, and control systemic inflamation may improve long-term outcomes in AD patients. However, to the best of our knowledge, no study has evaluated the effectiveness of early intervention on atopic march using systemic therapy in high-risk infants. This narrative review addresses the latest knowledge of systemic treatment, including Th2 cytokine receptor antagonists and Janus kinase inhibitors, for children with moderate to severe AD that is refractory to topical treatment.

Keywords: Atopic dermatitis; Biological products; Child; Cytokines; Etiology; Janus kinases; Therapeutics.

Fig. 1.

Pathophysiology of atopic dermatitis. The pathophysiology of atopic dermatitis is complex and multifactorial and caused by the interaction among epidermal barrier dysfunction, immune dysregulation, itching, and microbiome dysbiosis. An impaired epidermal barrier is characterized by downregulated epidermal barrier structural proteins, intercellular lipids and enzymes, decreased AMPs, increased skin pH, and reduced skin microbiome diversity with a greater abundance of Staphylococcus aureus. As a result, antigens can easily penetrate, transepidermal water loss is increased, and epithelial-derived cytokines (alarmins) such as TSLP, IL-33, and IL-25 are released. Epithelial-derived cytokines are critical mediators of type 2 inflammation through activation of DCs and ILC2s. TSLP activates OX40 ligand-expressing dermal DCs to induce naive T cells to differentiate into inflammatory Th2 cells that produce IL-4, -5, -13, and -31. Th2 cytokines including IL-31 and TSLP are potent pruritogens. Th2 and Th22 cells play a major role in AD, and Th1 and Th17 cells have been suggested to play roles as well. AMPs, antimicrobial peptides; Ag, antigen; TEWL, transepidermal water loss; TSLP, thymic stromal lymphopoietin; IL, interleukin; DC, dendritic cells; ILC2, type 2 innate lymphoid cells; Th1, T helper 1; Th2, T helper 2; IgE, immunoglobulin E.

Fig. 2.

Proportion of moderate to severe atopic dermatitis children aged 6 months to 17 years who achieved an EASI 75 on dupilumab treatment. The figure shows the 3 blinded placebo controlled studies that evaluated the efficacy of dupilumab treatment for 16 weeks in children aged 6 months to 17 years. The label on each bar shows the treatment regimen. q2 wk, every 2 weeks; q4 wk, every 4 weeks; EASI 75, 75% reduction in eczema area and severity index.

Fig. 3.

Forest plot of proportion of adolescents with moderate to severe atopic dermatitis who achieved EASI 75 for each treatment. The figure shows the odds ratio and 95% confidence interval (CI) for patients who achieved an EASI 75 in studies evaluating the efficacy of biologics and Janus kinases in adolescents treated for 12–16 weeks. *Adult studies included 10%–22% of adolescents. q2 wk, every 2 weeks; q4 wk, every 4 weeks; AD, atopic dermatitis; EASI 75, 75% reduction in eczema area and severity index; TCS, topical corticosteroid.

Fig. 4.

JAK-STAT pathway and JAKs paired with cytokine receptors in atopic dermatitis. When a cytokine binds to the intracellular domains of cytokine receptors, a conformational change is induced and JAK-tyrosine kinases are activated, resulting in the phosphorylation of tyrosine residues in the receptor’s intracellular domain. The phosphorylation of receptor subunits allows the recruitment of STATs. Phosphorylated STATs are activated, dimerized, and translocated to the nucleus to regulate the expression of target genes. JAK, Janus kinases; STAT, signal transducers and activators of transcription.